This double-blind, placebo-controlled, parallel-design multi-center clinical trial was developed to determine the impact, if any, of levodopa on the natural history of Parkinson's disease (PD). In essence, there is a serious question whether levodopa, the most important and powerful drug available to treat the symptoms of PD, hastens the underlying progression of the disease in spite of its symptomatic benefit or whether it has no effect, or even slows the rate of progression. The design is that of a dose-response test of levodopa and matching placebo in patients with PD at its earliest stage, i.e., a stage where the symptoms are so mild that symptomatic treatment is not required. Enrolled subjects are assigned placebo or one of three doses (12.5/50, 25/100, 50/200 mg tid) of carbidopa/levodopa which they take for 40 weeks (9 months), followed by a two-week washout period. No other anti-Parkinson medication is allowed in the study. At the end of the washout period the blinded Primary Rater, who examined the subject at baseline and who has had no other contact with the subject over the next 42 weeks, re-examines the patient. The primary outcome variable is the rate of change of severity of PD in the four treatment arms based on a dose-response curve. Severity is measured clinically using the Unified Parkinson's Disease Rating Scale (UPDRS). The blinded institutional treating investigator evaluates subjects throughout the study and adjusts the frequency of dosings or adds specified antidote drugs to overcome complications from study drug when judged to be clinically required. No symptomatic anti-PD drug will be openly added during the trial. There are a number of secondary outcome variables as well: monitoring the longduration and the short-duration benefit of levodopa, studying fatigue in PD, the effect of levodopa on depression, the effect of caffeine on PD, and the development of adverse effects of levodopa. Knowledge gained from this study will address the most common concern of patients, families and clinicians, namely should levodopa be delayed as long as clinically feasible or be used as early as possible. NIH funding for this clinical trial began on January 1, 1998, and is scheduled to be completed on December 3 1, 2000. We are not able to complete this clinical trial within this time frame, and with this application we are requesting an extension of the deadline with additional ftinding to complete the study.